Cinnamyl quaternary ammonium compounds



Patented Sept. 2, 1952 CINNAMYL 1 09392 t QUATERNARY. AMMONIUM COMPOUNDS Frank S. Crossley, Collingdale, Pa., assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing. Application April 27, 1950, Serial No. 158,590

This invention relates to antiseptic and germicidal compounds, and more particularly to quaternary ammonium compounds having these properties, and having the general formula:

in which R is an aliphatic radical containing from 8 to 12 carbon atoms. R can be a normal alkyl chain, or it can contain a terminal cyclohexyl radical. X is a chlorine, iodine or bromide.

A feature of the invention resides in the discovery that the presence of the cinnamyl radical in the compounds unexpectedly enhances its bactericidal action. Compounds of a somewhat analogous structure have been known, but they have not included the cinnamyl radical of this invention.

Aqueous solutions of these compounds are valuable as antiseptics and germicides. For example, they may be used as mouth washes and for topical application. Due to the unusually high activity of the compounds, very dilute aqueous solutions may be used and they possess the consequent distinct advantage of lacking a, strong taste or odor.

The compounds of the invention may be made by starting with the readily obtainable alkylbenzene having a primary amino group attached to the a. or carbon, wherein the aliphatic radical has from to 14 carbon atoms. As mentioned above in defining the invention, the ali-.

phatic radical may be a straight chain or may have a' terminal cyclohexyl group. I This primary amine is converted to the cor responding tertiary amine by dimethylation with formic acid and formaldehyde according to known methods. One such method involves the addition of one mol of the selected amine dropwise to about 5 mols of formic acid (90%) to obtain the formate of the primary amine and then adding rapidly, during about a minute, about 2.2 mols of formaldehyde (36%). This should all take place with the reaction flask immersed in a cool water bath while the mixture is stirred continuously. The mixture is allowed to react without heating for an additional fifteen minutes, then "cautiously warmed until a vigs Claims. (Cl. 260567.6)

orous reaction commences as is evidenced by considerable foaming due to the evolution of carbon dioxidelfi The reaction is thereafter controlled to'fmaintain gentle refluxing conditions by the application of heat or a cool water bath, as required. The vigorous reaction subsides in about fifteen minutes but the stirring should be continued and the flask should be heated on a steam bath for about an additional seven hours.

The tertiary amine is'then isolated by conventional methods as-follows: The mixture is diluted with water and made strongly alkaline with an excess of sodium or ammonium hydroxide solutions. The oil that separates is dissolved in benzene. The benzene solution is thoroughly washed with water and then benzene is removed by distillation. The tertiary amine is separated from the residue by fractional distillation in vacuum.

The tertiary amine is then quaternized by allowing it to react, preferably at room temperature, with an equimolecular amount of a cinnamyl halide until the resulting solid is completely soluble in water. The quaternary ammonium salt isthen purified by crystallization from an appropriate solvent or solvent mixture.

These compounds were subjected to the United States Food and Drug Administrationmethod of testing antiseptics and disinfectants, essentially as described at pages 2 through the. middle of page 10 of the United States Department of Agriculture Circular No. 198 dated December 1931. The culture used was Staphylococcus aureus F. D. A. No. 209-A. The effective aqueous dilution represents the greatest dilution of one gram of the specific compound capable of killing the.

organism in ten minutes, but incapable of killing it in five minutes. This follows the explanation contained between thetwo tables on page 8 of the Circular No. 198. Tests are made at 37 C.

As the tertiary amine, that is, the a-phenylor a-benzylalkyl dimethylamine, is readily made accordingto the above procedure or is obtainablecommercially, the tertiary amines are employed as starting materials in the following examples.

EXAMPLE '1 To a lass jar is added '.36 -.grams (0.25 mol) 'of' 'alpha-phenyldecyl-dimethylamine and 38.15

the formula:

GTE-09H and melts at 73-74" C. (uncorrected).

The effective aqueous dilution when tested as above described was 1:80,000.

EXAlWPLE 2 The corresponding iodide is made by using an ;by reacting alpha-benzyldodecyl-dimethylamine 14.17 grams (0.046 mol) with cinnamyl chloride 7.015 grams (0.046 mol). The compound has the equivalent amount of cinnamyl iodide instead of cinnamyl chloride.

EXAMPLE 3 Alpha-phenyldodecyl dzmethyZ-cinnamylammoaiumphloride p This compound wasiprepared as in" Example 1, by reacting alpha-phenyldodecyl dimethylamine 28.95, grams 7 (0.1 moll with cinnamyl chloride 15.25 grams (0.1 mol) Thecompound hasthe formula: I

- ?fi-Cufizs j I, lessor-H3 r ou=ou.om I (:1 and melted at 834314 (un'c iorrectecl). Efiiective aqueous dilution 1:192,000.

4 The corresponding bromide is made by substituting an equivalent amount of einnamyl bromide. v I

v EXAMPLE 5 v Air/hmuttefiylttmdecyi-dimethyl cinnamyle ommoniumchloride This compoundwas prepare d as in Example. 1, by reacting yalpha-phenyltetradecyl-dimethylamine 6.5 grams (0.02 mol) with ciunamyl chloride 3:13 grams .(0.02 mol)' The compound has oH s om and. melted at 76 77 c... (uncorrected) Effective aqueous. dilution l:70 000 The c orresp cuuding iodide is made by substi tilting an equivalent amount of, cinnamyliodide,

This compoundwasprepared; as in Example 1, by reacting (l-phenyl-fi-cyclohexyl-hexyl)-dimethylamine 'l' izs'r. grams (0.05 mol) [with 4 oinnamyl chloride 7.63 grams (0.05 mol). compound has the formula:

CHz-N-CH:

and melted at 137-138 C. (uncorrected).

Effective aqueous dilution 1 :180,0 00.

JEXAMPLE a The corresponding bromide is made by substituting an equivalent amount of cinnamyl bro- The EXAMPLE 9 .AZphw-beneuldodecyl-dimethyl-cmnamylammonium chloride This compound was prepared as in Example 1,

formula l QQQHLTRCHHH 'sxaiupnnloi.

Alpha-heresyitetmdecgzl-dimethylecimzamylammonium iodide By euuilnolecular weights of alpha-benzyitetradecyl dimethylamine andcinnamyl iodide, the compound having'the' followingformula is: oh-

Instead ofmakingrthe single compoundof one ofthe above examples, a mixture of them may be made by simultaneousquaternization of a mixture of. tertiary amines; Forexample, instead of the separate tertiary amines used asstartingv materials in Examples; 1, 3- and 5, a mixture of these: tertiary aminea such'asis obtained from cocoanut -olls,, may?v beemployed; The alkyl radicals present in cocoanut; oils predominantly contain 1.0;. 1-2 and ld'carbon atoms, suchas are present in the so-called lorolccmpounds; These alkyl derivatives may be employed to make the primary amines, thenthe tertiary amines and finally the quaternary ammonimn'compounds of the iuvene tion, asya less costlymixture. I

It will :be noted" that'aqueous solutions of'thecompounds-of therinventiorr may be as dilute as 1380,0002 and still :maintain satisfactory germioidalactivity'. ..:This' isto be contrasted with simipounds isjasiollo-wst p V al aphenyl d'odecyl aim'etn i-auyiammonium bfomide 5 Alpha phenyldecyl dimethyl-benzylammonium chloride 1225,000 Alpha phenyldecyl dimethyl cinnamyl-ammonium chloride 1 80,000 (1 phenyl 6 cyclohexyl hexyl) -dimethyl cinnamyl ammonium chloride 1:180,000

This application is a, continuation in part of application Serial No. 2,324, filed January 14, 1948, by Moore and Crossley, now abandoned.

What is claimed is:

1. Quaternary ammonium compounds having the formula Q T2H3)R is a l-phenyl-alkane, the

portion of which contains from 10 to 14 carbon atoms and is selected from the group consisting ammonium chloride.

5. (1-phenyl-6-cyc1ohexy1) dimethyl cinnamyl-ammonium chloride.

6. Alpha-benzyldodecyl dimethyl cinnamylammonium chloride.

FRANK S. CRO SSLEY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Mettler et al. Mar. 1'7, 1942 OTHER REFERENCES Voigt et al., Chem. Zent. 1940 (II), P. 655.

Number 

1. QUATERNARY AMMONIUM COMPOUNDS HAVING THE FORMULA 